Highlights of This Issue

Role of Ribosomal Protein RPS2

Pioneer work showed Lin28a/28b targeting of pre-let-7g for degradation plays an important role in dysregulation of miRNA expression in cancer. Wang and colleagues discovered that the ribosomal protein RPS2 is aberrantly overexpressed in prostate cancer cells and specifically binds the stem loop domain (i.e., UAGGGUCAC) of pre-let-7a-1, blocking pre-let-7a-1 processing to let-7a/let-7f. Consequently, RPS2 promoted ras/myc expression to increase the tumorigenesis of primary and malignant prostate cells in vitro and in vivo. The overexpression of let-7a/7f in pBABE.pre-let-7a transfected PC-3ML variants blocked tumorigenesis, suggesting that RPS2 functions in a negative-feedback loop, which downregulates let-7a/7f to promote oncogene-dependent tumorigenesis.

L1 Induces Colon Cancer Metastasis but Not EMT and CSC Markers

Activation of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) was implicated in the metastasis of various human tumors. Gavert and colleagues investigated the necessity for changes in EMT and CSC markers during L1-mediated metastasis of colorectal cancer (CRC) cells. The elevation or suppression of L1 levels had no effect on EMT and CSC markers in CRC cells and tissue. When EMT was induced in CRC cells by Slug or Twist overexpression, this was insufficient (unlike L1 overexpression) to cause metastasis. NF-κB signaling was essential for L1-mediated metastasis of CRC cells implying its critical role in human CRC progression.

Nontranscriptional Regulation of HIPK2 by MYCN

MYC oncoproteins are a family of transcription factors involved in the control of pivotal processes such as cell cycle progression, differentiation, carcinogenesis, metabolism, and angiogenesis. Although deregulation of their expression was shown to be critical in several human neoplasia, MYC overexpression might also lead to apoptosis. By gain and loss of function experiments, Petroni and coworkers show that sensitization to apoptosis by MYCN requires p53, its phosphorylation at serine 46, and the induction of the p53 proapoptotic kinase HIPK2. MYCN leads to a nontranscriptional HIPK2 accumulation by inhibiting its degradation via an ATM-dependent DNA damage response. Importantly, the HIPK2-p53 pro-apoptotic pathway is conserved in a large number of MYCN-amplified human neuroblastomas, where it can be targeted by the p53 reactivating compound Nutlin-3. Indeed, Nutlin-3 further induces HIPK2 accumulation, p53S46 phosphorylation, and a dramatic level of apoptosis, in MYCN-amplified neuroblastoma cells, suggesting its possible use in the treatment of an otherwise largely untreatable neoplastic disease.

Cbp in Lung Cancer

The transmembrane adaptor Cbp/PAG1 is a suppressor for c-Src-induced cell transformation. Kanou and colleagues examined its relevance to human lung cancers. Cbp was widely downregulated in non-small cell lung cancer (NSCLC) cells. Re-expression of Cbp suppressed growth, invasion, and metastasis of NSCLC cells, particularly in which c-Src is upregulated. Furthermore, there was an inverse correlation between Cbp levels and the ability of lymph node metastasis in lung cancers. These results indicate that Cbp acts as a suppressor for tumor progression in a subset of NSCLC. Thus, mechanistic analysis of Cbp downregulation would offer new opportunities for therapeutic intervention in NSCLC.